Diagnosing mucopolysaccharidosis IVA

Abstract

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.

Dried Blood Spots Allow Targeted Screening to Diagnose Mucopolysaccharidosis and Mucolipidosis

“…), leading to diminished a-iduronidase activity while the activities of the other enzymes remain within the normal range, as might be the case in the two patients. Consequently, confirmatory testing of an independently obtained second DBS is important to validate the initial results of the enzymatic analysis (Wood et al 2013). As no second DBS has been received for the two putative MPS I patients without identifiable mutations in the IDUA gene, the results of their enzymatic tests should be considered tentative.…”

“…In such regions, it may not be feasible to transport whole blood or other tissue samples, in order to confirm the DBS-based diagnosis. In the latter case, a second independently collected DBS would be needed to confirm the diagnosis (Wood et al 2013). To elucidate the diagnostic efficacy of the DBS method to detect affected individuals, a study for MPS I, MPS II, MPS VI and ML II/III is necessary with patients of confirmed diagnosis, especially as the sensitivity of our screening assay remains unknown because of the small group of patients diagnosed.…”

Diagnosis of Morquio-A patients in Mexico: How far are we from prompt diagnosis?

“…It has a wide clinical spectrum, that may not be easy to recognize from other non-systemic skeletal dysplasias, which represents a challenge in diagnosis in young patients (3,4). This condition has progressive multisystem dysfunction and impaired functional capacity.…”

“…Since Morquio-A patients have not primary neurological involvement (1,2,4,5), an early detection, as well as early treatment could prevent the severe functional impairment seen on these patients, improving outcomes and extending their autonomy (2,(7)(8)(9). Generally, before definitive diagnosis, patients are delayed or misdiagnosed due the lack of knowledge about the disease (10,11).…”

“…Early onset findings are kyphosis, scoliosis, growth retardation and altered gait (4,14). The vast majority of papers detail clinical features but only few mention the age of onset.…”